Alzheimer's disease (AD) is a slow, progressive, and ultimately fatal neurodegenerative disorder, clinically characterized by a noticeable cognitive decline defined by a loss of memory and learning ability, together with a reduced ability to perform basic activities of daily living, and a diverse array of neuropsychiatric symptoms. It mainly affects older people. After 65, the likelihood of developing AD doubles every 5 years. Some 35 million people worldwide, i.e. about 0.5% of the world's total population, are suffering dementia, in most cases AD. AD is among the top ten leading causes of death in developed countries, but the only one among them that cannot be cured, prevented or even slowed down. As a consequence of its increasing prevalence and devastating effects, AD is currently affecting every health system in the world. The total worldwide estimated cost associated with AD accounts for approximately 1% of the world's gross domestic product. Worryingly, the figures associated to AD are rising both in terms of mortality and prevalence. Thus, death rates from other major diseases have dropped since 2000, whereas the number of deaths from AD has risen 66%. Also, it is estimated that the prevalence of AD will double every 20 years, reaching 66 million people worldwide by 2030 and 115 million by 2050. Consequently, there is an acute need for effective pharmacotherapies of AD.
Therapeutic interventions currently available for AD, namely the acetylcholinesterase (AChE) inhibitors donepezil, galantamine and rivastigmine and the glutamate NMDA receptor antagonist memantine, are merely symptomatic. These drugs compensate for neurotransmitter deficits that arise at the end of the neurotoxic cascade of AD as a consequence of the neuronal death and are responsible for the cognitive decline of AD patients. In contrast, most drug candidates under clinical development have been designed to hit one of the biological targets involved in the early pathogenic events of the neurotoxic cascade of AD that are responsible for the neuronal death, mainly the formation of the beta-amyloid peptide (Aβ), which involves the proteolysis of the amyloid precursor protein by the sequential action of the enzymes β-secretase (BACE-1) and γ-secretase, and the subsequent aggregation of Aβ into toxic oligomers and fibrils. Disappointingly, the most advanced drug candidates in clinical trials hitting these biological targets have failed in the past years. The clinical development of the Aβ-antiaggregating compound tramiprosate and the γ-secretase modulator tarenflurbil, whose launching was expected by 2009/2010, was discontinued in advanced Phase III trials shortly before these dates due to efficacy issues. Analogously, clinical development of the promising BACE-1 inhibitor LY2811376 was discontinued in Phase I trials in 2011 due to toxicity findings observed in parallel longer-term preclinical studies in mice that are unrelated to BACE-1 inhibition.
Even though BACE-1, γ-secretase and Aβ aggregation, as well as tau aggregation or hyperphosphorylation or oxidative stress, among others, remain viable targets, it seems that they should be hit in a different approach. It is becoming increasingly apparent that diseases, in general, and complex diseases as AD, in particular, are not linear processes but rather complex networks of interconnected protein targets, with alternative, redundant, compensatory signaling pathways that render ineffective the modulation of a single target of the pathological network by compounds as those anti-Alzheimer drug candidates that are recently failing in clinical trials. Conversely, simultaneous modulation of several targets involved in the pathological network should result in a more efficient therapeutic approach. Thus, simultaneous blockade of several important nodes of the pathological network of AD is emerging as a therapeutic approach for efficiently interfering the underlying mechanisms of the disease.
The multitarget approach to AD can be accomplished by means of single compounds that are structurally suited to hit different biological targets.
In vitro inhibitory activities of AChE and AChE-induced Aβ aggregation have been reported for different families of dual binding site AChEIs. The catalytic site of AChE is involved in the hydrolysis of the neurotransmitter acetylcholine, whereas the peripheral site is involved in a binding process with Aβ that accelerates the aggregation of this peptide. Thus, simultaneous blockade of the catalytic and peripheral sites of AChE by dual binding site AChE inhibitors (AChEIs) results in the simultaneous modulation of two important targets of AD pathology, namely Aβ aggregation and the cholinergic deficit. Among the compounds disclosed having in vitro inhibitory activities of AChE and AChE-induced Aβ aggregation are memoquin (cf. e.g. A. Cavalli et al., “A Small Molecule Targeting the Multifunctional Nature of Alzheimer's Disease”Angew. Chem. Int. Ed. 2007, vol. 46, pp. 3689-3692) or some hybrid compounds having the 5,6-dimethoxy-2-[(4-piperidinyl)methyl)]-1-indanone moiety of donepezil (or the indane derivative thereof) and a unit of tacrine or huprine as the peripheral to mid-gorge and active site interacting moieties (cf. WO2007122274 or WO2011076969, respectively). There is only one example of dual binding site AChEI in clinical trials for Alzheimer's disease, namely Noscira's NP-61, which entered phase I clinical trials in 2007. For this compound a potent AChE inhibitory activity and Aβ-antiaggregating effect have been reported.
Therefore, despite all the research efforts invested in the past, there is still an important need to find compounds for the treatment of Alzheimer's disease which could modify the course of AD, stopping or slowing down the disease progression.